UNC45A Deficiency (Osteo-Oto-Hepato-Enteric Syndrome)

Osteo-oto-hepato-enteric syndrome (O2HE) due to biallelic coding variants in the UNC45A gene, with Aagenaes syndrome (cholestasis-lymphoedema 1) as an allelic disorder

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

1. Introduction

Definition and scope

UNC45A deficiency designates the set of diseases caused by biallelic loss of function of the UNC45A gene, which encodes a myosin co-chaperone. The form described with variants in both copies of the coding region is osteo-oto-hepato-enteric syndrome (O2HE), whose name brings together the four organs affected: bone (bone fragility with fractures), ear (sensorineural hearing loss), liver (intrahepatic cholestasis) and intestine (congenital diarrhoea) [1]. OMIM defines the disease as a variable combination of these four components, with mild developmental delay and intellectual disability in some patients, and lists it as "osteootohepatoenteric syndrome" (OOHE), with O2HE as an alternative symbol [2]. Variability is the rule: no patient in the original series had all four manifestations, and the clinical definition rests on a core of signs present in at least three of the first four patients [1].

The same gene causes a second disease, Aagenaes syndrome or cholestasis-lymphoedema 1 (LCS1), in which one of the alleles (or both) is a 5' untranslated region variant that reduces expression without altering the protein [8]. The two diseases are distinguished by genotype and phenotype: Aagenaes combines neonatal cholestasis and lymphoedema and has no diarrhoea, hearing loss or bone fragility, whereas O2HE has diarrhoea, hearing loss and bone fragility and no lymphoedema [8, 20]. Aagenaes syndrome is covered here only in the aspects relevant to the gene's diseases as a whole.

Historical overview

The syndrome was described in 2018 by Clothilde Esteve, Ludmila Francescatto, Perciliz Tan and colleagues from Marseille, Dijon, Paris, Brussels and Duke University, who studied four patients from three families with congenital cholestasis, diarrhoea, bone fragility with recurrent fractures and deafness [1]. The first patient was identified in a research programme of more than 500 undiagnosed patients, by trio exome sequencing, and the others were gathered through a genotype-first approach after the same gene was found in a second family; the authors confirmed loss of function by immunodetection of the protein in patients' cells and by zebrafish models, and proposed the name O2HE [1]. The work circulated as a preprint in 2017 and was funded in part by a French association of patients on parenteral nutrition, the Association Romy [1].

In 2022, Rémi Duclaux-Loras and colleagues from the Imagine Institute and Necker Hospital, in Paris, with groups from Innsbruck and Oxford, described six patients from five families with severe congenital diarrhoea and showed that the enteropathy has the histological and ultrastructural features of microvillus inclusion disease (MVID) and that myosin VB is a client of the co-chaperone UNC45A [3]. In the same year, the Groningen group showed that UNC45A depletion reduces myosin Vb in intestinal and hepatic cells and reproduces the cellular changes of MVID [25]. In 2023, Runar Almaas and colleagues identified the 5'UTR founder variant c.-98G>T in all 26 Norwegian patients with Aagenaes syndrome studied, resolving a disease described in 1968 [8, 26]. Between 2022 and 2026, isolated cases were published from China, Russia, the United States, Palestine and the Netherlands, including the first adults successfully treated with the ileal bile acid transporter inhibitor odevixibat [12–19]. In 2025 and 2026, functional studies explained the mechanism of two recurrent variants: p.(Leu237Pro) alters the interaction of the co-chaperone with non-muscle myosin II, and p.(Arg98Trp) weakens binding to the chaperone HSP70 and prevents trafficking of the bile salt export pump (BSEP) to the canalicular membrane [20, 27].

Milestones of the molecular discovery

Current nomenclature and classifications

The designation O2HE is that of the founding paper and the clinical literature; OMIM uses OOHE as the main symbol and O2HE as an alternative [1, 2]. Duclaux-Loras and colleagues proposed that UNC45A deficiency be regarded as a non-classical form of MVID, and subsequent reviews include UNC45A among the four MVID genes, alongside MYO5B, STX3 and STXBP2 [3, 29, 30]. In a liver-centred classification, the disease belongs to the group of low- or normal-GGT intrahepatic cholestases linked to myosin VB-dependent canalicular trafficking, alongside MYO5B-related cholestasis and Aagenaes syndrome [8, 20]. The chapter on disorders of cellular trafficking in the Saudubray textbook lists UNC45A among the vesicular trafficking defects in four groups of extraneurological manifestations: structural bone abnormalities, chronic liver disease, gastrointestinal signs and deafness [31].

Variant numbering requires attention. The founding paper described the variants on transcript NM_001039675.1, which encodes an isoform 15 amino acids shorter at the start of the protein (the first 17 residues MTVSGPGTPEPRPATPG of isoform 1 correspond to MT in isoform 2); subsequent work, ClinVar and this article use the MANE Select transcript NM_018671.5 [1, 9, 29]. Therefore, the p.Arg83Trp variant of Esteve and colleagues is the same p.(Arg98Trp) described later in China and the Netherlands, presented in 2022 as novel [7, 12].

Entities within scope

O2HE is defined by the presence of two coding loss-of-function variants in UNC45A in a patient with at least one of the intestinal, hepatic, auditory or bone components [2, 20]. Aagenaes syndrome is defined by neonatal cholestasis with lymphoedema and at least one 5'UTR allele [8]. Patients with an isolated MVID phenotype and biallelic UNC45A variants belong to the O2HE spectrum and not to a separate entity [3, 17].

2. Molecular Genetics and Pathophysiology

The gene and the protein

The UNC45A gene is located at 15q26.1 (GRCh38 15:90,930,180–90,954,093) and encodes a 944-amino-acid, 103.5 kDa cytoplasmic protein, with 94% identity to the mouse protein and 56% to the paralogue UNC45B [5]. The original description of the gene counted 20 exons over 21.4 kb, and the annotation used by Duclaux-Loras and colleagues counts 23 exons [3, 5]. The protein belongs to the UCS family (UNC-45/CRO1/She4p), conserved since invertebrates, and has four regions: an N-terminal tetratricopeptide repeat (TPR) domain (residues 1–143), which binds the chaperones HSP90 and HSP70; a central armadillo-type repeat (ARM) domain (144–385); a "neck" domain (386–557); and the C-terminal UCS domain (from residue 558), which binds the motor domain of myosins [1, 3, 20]. Invertebrates have a single unc-45 gene, expressed in and outside muscle; in vertebrates, an ancestral duplication gave rise to UNC45B, restricted to striated muscle, and UNC45A, ubiquitously expressed, which explains the absence of myopathy in patients with O2HE, who have normal creatine kinase [1, 3]. UNC45A expression has been detected in the mouse uterus, large intestine, kidney, spleen, lung, brain, liver and ovary, and the human protein also binds the progesterone and glucocorticoid receptors, regulating the progesterone receptor chaperone pathway [5].

Function: myosin co-chaperone

UNC45A acts with the chaperones HSP90 and HSP70 in the folding, stability and positioning of myosin motor heads, preventing their aggregation [3, 20]. In Caco-2 intestinal epithelial cells, immunoprecipitation of UNC45A followed by mass spectrometry identified 111 associated proteins, among them four HSP90 proteins, actins and nine myosins, including unconventional myosin VB (MYO5B); in the absence of UNC45A, proteasome inhibition caused myosin VB aggregates to appear, a sign of misfolding [3]. Myosin VB is the motor that, associated with the GTPases RAB11A and RAB8A, transports recycling endosomes to the apical membrane of the enterocyte and to the canalicular membrane of the hepatocyte; it is the protein altered in the main form of MVID and in one form of progressive familial intrahepatic cholestasis [3, 32]. UNC45A also regulates non-muscle myosin II (NMII), needed for stress fibres, membrane recycling and cell migration [27].

Intestinal mechanism

Loss of UNC45A reproduces MVID in the intestine. In duodenal biopsies from three patients, villous atrophy without inflammation was accompanied by subapical accumulation of CD10 and diffuse periodic acid–Schiff (PAS) staining; transmission electron microscopy showed erosion, reduction or malformation of apical microvilli, subapical pleomorphic vesicles, PAS-positive "secretory granules", cytoplasmic microvillus inclusions, ectopic basolateral microvilli and enlarged lysosomes [3]. Caco-2 cells lacking UNC45A formed cysts with several cavities instead of a single lumen, a defect corrected by the normal protein and not by the patients' alleles; intestinal organoids derived from the patients' induced pluripotent stem cells had abnormal architecture, microvillus inclusions and mislocalised apical sodium transporters (the NHE3 exchanger and the chloride-bicarbonate exchanger DRA), with displaced RAB11 protein [3]. In the mutant zebrafish, loss of UNC45A erased the folds of the anterior intestine, delayed intestinal transit and gave rise to intracellular villin compartments, basolateral RAB11 and shorter microvilli [1, 3]. UNC45A depletion reduces the amount of myosin Vb in intestinal and hepatic cells, and reintroduction of myosin Vb restores the positioning of recycling endosomes and microvillus development [25].

The function of the cystic fibrosis transmembrane conductance regulator (CFTR) is debated. Duclaux-Loras and colleagues found apical CFTR correctly localised and a normal short-term response of the organoids to forskolin [3]. In 2026, primary mucosal organoids from a patient homozygous for p.(Glu728Lys) grew less and swelled less than three controls after 5 µM forskolin, with a difference from 12 hours of observation onwards, suggesting a contribution of CFTR [33].

Hepatic mechanism

In the liver, the defect translates into a failure of BSEP trafficking to the canalicular membrane. In a patient with the variants p.(Arg98Trp) and p.(Gln198Ter), immunofluorescence showed BSEP mislocalised in cytoplasmic puncta only in hepatocytes of the mid-zone of the acinus, with normal localisation near the vessels [18, 20]. In HepG2 hepatocytes lacking UNC45A and re-expressing the p.(Arg98Trp) form, MYO5B was concentrated in a restricted region near the canaliculus, and BSEP accumulated in MYO5B+/RAB11A+ endosomes that did not reach the canalicular membrane [20]. The Arg98Trp substitution lies in the TPR domain, near the chaperone-binding site, and weakens the interaction with the HSP70 proteins (HSPA1A and HSPA8) and with MYO5B; another variant designed to prevent HSP70 binding and pharmacological inhibition of HSP70 reproduced the defect [20]. HSPA1A expression in the liver is zonated and lower in the mid-zone of the acinus, the same zone where BSEP was mislocalised, which led the authors to propose that local HSP70 availability conditions the phenotype [20]. A finding relevant to genetic interpretation is that complete loss of UNC45A in hepatic cells eliminated MYO5B without altering BSEP: as in MYO5B disease, in which loss of the protein does not cause cholestasis and missense variants do, cholestasis appears to result from a myosin VB that is present but dysfunctional and interferes with endosome trafficking [20]. Multidrug resistance-associated protein 2 (MRP2) remained correctly localised in cells and in biopsies from patients with O2HE, unlike what is described in Aagenaes syndrome, in which BSEP and MRP2 are both mislocalised [8, 20].

Ear and bone

The mechanism of the hearing loss and bone fragility has not been demonstrated. UNC45A is needed for the folding of myosin XVA (MYO15A), indispensable for the elongation and maintenance of hair cell stereocilia, and MYO15A variants cause DFNB3 deafness; Wang and colleagues propose that the hearing loss results from failure of stereocilia myosins [12]. For bone fragility, the predicted high expression of the gene in bone was one of the arguments of the discovery, with no published functional model [1]. In the patients with fractures in the original series, calcium, phosphate, parathyroid hormone (PTH) and vitamin D were normal, which rules out a purely deficiency-based explanation [1].

Inheritance

O2HE is autosomal recessive, with segregation confirmed in all families studied [1–3]. Carriers are healthy, although the lymphoblastoid lines of the heterozygous parents of family C had 45% and 52% less protein than controls [1]. In the case of the p.(Leu237Pro) variant, co-expression of the normal allele attenuates the formation of abnormal oligomers, which explains the absence of disease in carriers [27]. In Aagenaes syndrome, the combination of alleles determines the phenotype: two 5'UTR alleles or one 5'UTR allele with one exonic loss-of-function allele cause Aagenaes, and two coding alleles cause O2HE [8]. OMIM also records, in the Aagenaes entry, mother-to-daughter transmission in a non-consanguineous British family, of unexplained mechanism [4].

Variant spectrum

Zhou and colleagues counted 19 variants associated with O2HE in the literature up to 2026: 12 missense, 5 nonsense, 1 frameshift and 1 in-frame deletion; only p.(Arg98Trp) lies in the TPR domain, six in the central domain, two in the neck and ten in the UCS domain, with none at residues in direct contact with myosin [20]. The following table brings together the published variants, normalised on the MANE transcript with VariantValidator and checked against ClinVar [7, 9].

The conversion of the Esteve and colleagues variants to the MANE transcript was performed in VariantValidator from the genomic coordinates, and ClinVar already records these variants with NM_018671.5 numbering [7, 9]. For the three variants of Fiedler and colleagues, published without a transcript, the conversion assumes isoform 2 numbering, and Zhou and colleagues cite the first as p.Leu757Pro, which confirms it [15, 20]. Three discrepancies remain documented in the literature: the maternal variant of family B appears as c.2581C>T in the figure and as c.2584C>T in the text; p.(Ala838Pro) appears as "c:2467G>C" in the 2022 text, whereas codon 838 begins at nucleotide 2512; and the c.1452delinsGC change, described with a premature stop 31 codons downstream, is normalised by VariantValidator as an insertion of a guanine with a stop 4 codons downstream [3, 5, 7]. The paternal variant of family B consists of two substitutions on the same allele, a correction that the journal never published, according to OMIM [5].

Several variants published as causal remain classified as of uncertain significance (VUS) by a single submitter in ClinVar, including p.(Arg98Trp), p.(Leu237Pro), p.(Val438Asp), p.(Arg241Ter) and p.(Arg819Ter) [9]. ClinVar also lists pathogenic or likely pathogenic loss-of-function variants with no associated published phenotype (for example c.239_240del, c.975del, c.2764dup, c.1027+1G>A, c.2073+1G>A and c.213+1G>C) [9]. In the gnomAD database, the frequencies of the recurrent variants are very low: 4/282,568 alleles for p.(Arg98Trp), 3.99×10⁻⁶ for p.(Leu237Pro) and 6.39×10⁻⁶ for p.(Glu728Lys) [5, 12].

Functional effect of the variants

The truncating variants p.(Arg241Ter), p.(Asp484GlufsTer4) and p.(Arg819Ter) produced no protein when expressed in HEK293T cells [3, 13]. In the lymphoblastoid lines of the four 2018 patients, the protein was reduced by 70% to 93%, and in the fibroblasts of one patient by 82%, with no detectable truncated fragments [1]. The missense variants p.(Thr230Arg), p.(Leu237Pro), p.(Glu728Lys) and p.(Ala838Pro) are expressed in amounts comparable to normal but do not correct the defect of cells lacking UNC45A, because of predicted or demonstrated structural alteration [3]. p.(Val438Asp) reduces protein stability [25]. p.(Leu237Pro) retains chaperone activity and prevents aggregation of non-muscle myosin II, but forms abnormally stable oligomers that prevent dissociation of the chaperone–myosin complex and inhibit myosin function, with altered transferrin recycling [27]. p.(Arg98Trp) acts through the HSP70 pathway described above [20]. In all patients with O2HE studied, at least one allele appears to retain some function or to produce an abnormal protein; up to 2026, no patient with two null variants had been published [1, 20].

Genotype–phenotype correlations, penetrance and modifiers

No robust genotype–phenotype correlation has been identified in O2HE, and the heterogeneity is comparable to that of MYO5B-related MVID [12]. The clearest distinction is between alleles: 5'UTR alleles, which reduce expression, give Aagenaes syndrome, and two coding alleles give O2HE [8]. Within O2HE, the three patients with p.(Arg98Trp) had cholestasis as the dominant or persistent manifestation, with diarrhoea that improved or became episodic, whereas the three patients homozygous for p.(Leu237Pro) had severe neonatal diarrhoea with dependence on parenteral nutrition, one of them with total enterectomy and another dying at 3 months [1, 3, 12, 18]. These observations come from very few patients and do not allow the individual course to be predicted. In MYO5B-related MVID, complete absence of the protein or early truncation is associated with predominant intestinal disease and mutant proteins with residual function with predominant liver disease, a pattern that may help to interpret the variability of O2HE [20, 32]. Esteve and colleagues accept that expressivity may depend on the effect of each variant in each tissue, on modifier genes and on epigenetic or environmental factors [1]. Penetrance in carriers is nil for the disease, and penetrance of the components in biallelic patients is incomplete: in 16 patients reviewed in 2026, diarrhoea was present in 87.5%, cholestasis in 81.3%, bone fragility in 37.5% and hearing loss in 31.3% [19].

Allelic disorders and related genes

The only established allelic disorder is Aagenaes syndrome, in which the c.-98G>T variant reduces UNC45A messenger RNA to about half in homozygotes and the protein to 57% of controls; in compound heterozygotes with an exonic loss-of-function allele, RNA falls to 37% and protein to 17% [8]. Healthy carriers of an exonic allele have 39% of protein, showing that the basal level does not explain the disease; the authors propose a threshold of UNC45A below which the hepatocyte does not respond to cholestasis triggers [8]. In 2025 a second 5'UTR variant, c.-88G>A, was described in two Turkish siblings with Aagenaes, in compound heterozygosity with the nonsense variant c.1591C>T p.(Arg531Ter) [34]. The paralogue UNC45B, expressed in striated muscle, causes myopathy, with no clinical overlap with O2HE [3]. The genes that share the pathway (MYO5B, STX3, STXBP2, USP53) cause MVID and low-GGT cholestases, and are the main genetic differential [20, 29].

3. Clinical Spectrum and Manifestations by System

Common syndromic description

The typical picture begins in the neonatal period or in the first weeks with intractable watery diarrhoea, icteric cholestasis or both, and is completed during childhood and adolescence with fragility fractures and sensorineural hearing loss, which may be detected only late [1, 3]. No manifestation is constant. In a review of 16 patients published in 2026, diarrhoea was present in 87.5%, cholestasis in 81.3%, developmental delay in 50.0%, bone fragility in 37.5% and sensorineural hearing loss in 31.3%; 13 of 17 patients (76.5%) were female and 4 (23.5%) had consanguineous parents [19]. The female predominance results from a small number of patients and has no known biological explanation; Zhou and colleagues do not expect sex differences [20]. The review by Imhann and colleagues, with 14 patients, considers cholestatic pruritus the most constant feature [18], and that of Sun and colleagues, with 13, considers diarrhoea the most constant manifestation, followed by neonatal cholestasis [17]. The counts differ because each review includes different cases and because the description of each patient depends on the age at which it was published.

Prenatal and neonatal period

In several patients the disease manifests before birth. In a Turkish female patient, ultrasound in the seventh month of gestation showed dilatation of the small intestine and colon, and the child was born weighing 2100 g five weeks before term, with intrauterine growth restriction [3]. In a Chinese girl, progressive intestinal dilatation from 33 weeks, with a maximum loop diameter of 2.3 cm, polyhydramnios (amniotic fluid index of 25 cm) and fetal growth restriction, led to suspicion of congenital chloride diarrhoea; she was born at 36+5 weeks weighing 2160 g, and the mother had had six early pregnancy losses [17]. A Palestinian boy was born at 36+2 weeks weighing 1460 g (−2.89 standard deviations), after growth restriction and oligohydramnios [16]. Prematurity was recorded in four of the 12 cases reviewed by Sun and colleagues, who accept an association with preterm birth and pregnancy losses without demonstrating it [17].

Intestine

The diarrhoea is watery, secretory and profuse, with onset between the first day and the first weeks of life [2, 3]. In the Duclaux-Loras series, all six patients had severe diarrhoea: one infant went into hypovolaemic shock at 3 weeks, total parenteral nutrition failed to control losses and total enterectomy was performed at 20 months to control fluid and electrolyte balance, with 12-hour cyclic parenteral nutrition maintained at 4 years; another patient underwent small bowel transplantation; two sisters had diarrhoea of 7 to 10 stools a day from birth, with metabolic acidosis, and one died of multiorgan failure at 3 months [3]. In a French patient, the diarrhoea required prolonged exclusive enteral nutrition, became intermittent and ceased at age 10 years [3]. In the original series, the European patient was dependent on parenteral nutrition from day 4 and remained so at 5 years, and in one of the Tunisian sisters the initial diarrhoea with parenteral and enteral nutrition resolved over time [1]. In milder forms, diarrhoea of 3 to 5 stools a day resolved at 6 months, or persisted with loose stools up to 6 times a day and admissions for dehydration throughout life [12, 18]. Biopsies show villous atrophy, sometimes mild, with brush border changes, subapical accumulation of PAS and CD10 and, on electron microscopy, microvillus inclusions [2, 3]. In two adults with villous atrophy, the diarrhoea did not change with treatment of the pruritus [15, 18].

In MVID in general, faecal losses reach 150 to 400 mL/kg/day, with severe dehydration, metabolic acidosis, renal impairment and hyponatraemia; urinary sodium and the fractional excretion of sodium are low and there is hyperaldosteronism with high urinary potassium [35]. In a systematic review of 336 patients with MVID of any genetic cause, intractable diarrhoea was present in 98.8% and 97.6% of patients with treatment data received total parenteral nutrition; UNC45A was the fourth gene by frequency, after MYO5B, STXBP2 and STX3 [30].

Liver

Cholestasis usually begins in the first weeks, with jaundice, acholic stools and, later, intense pruritus [1, 18]. GGT is normal or low in most (for example 27 U/L with total bilirubin of 175 µmol/L and direct bilirubin of 137 µmol/L on day 28 in one patient), but was raised in at least two patients (one of the Tunisian sisters and the Chinese boy, with 81 U/L for an upper limit of 32 U/L) [1, 12, 18]. Alkaline phosphatase may be very high (902 U/L on day 28) and serum bile acids rise markedly (217 µmol/L at 3 months; more than 1350 µmol/L in an adult relapse) [12, 15, 18]. The course follows three patterns in the sources. In the first, the neonatal jaundice resolves and the patient remains well: the neonatal liver failure of a Turkish girl resolved at 4 months, and the Chinese boy's bilirubin normalised at 6 months [1, 12]. In the second, the jaundice disappears at 2.5 to 3 years but raised bile acids with intractable pruritus persist, as in the Tunisian sisters, who underwent partial internal biliary diversion at ages 12 and 19 years [1]. In the third, recurrent type, episodes of jaundice, pruritus and weight loss recur 2 to 3 times a year, with normal biochemistry between them, and the picture was diagnosed as benign recurrent intrahepatic cholestasis or as progressive familial intrahepatic cholestasis type 1 before the genetic diagnosis [15, 18]. In one patient, the adult episodes coincided with starting combined oral contraceptives [15].

Liver biopsies show cholestasis, sometimes with ductular proliferation or duct paucity, mild periductal inflammation or pericellular and periductal fibrosis with ballooned hepatocytes and Mallory-Denk bodies [2, 6, 18]. A North American patient had three biopsies up to age 3 years with intrahepatic cholestasis and mild fibrosis [15]. The facies may resemble that of Alagille syndrome [14].

Ear

The hearing loss is sensorineural and bilateral and ranges from moderate to profound [1, 16, 18]. The age at detection varies: in the fifth year of life, in adolescence, in childhood with a need for cochlear implants, at 11 months by brainstem auditory evoked potentials, or only at 31 to 33 years, after the genetic diagnosis [1, 15, 16, 18]. The language delay of the first patient described was attributed in part to the deafness [1]. In a Chinese boy, auditory evoked potentials were normal at 3 months (wave V threshold of 25 dB HL) and repeat hearing testing at 12 months was also normal; the table in the paper records hearing loss in this patient, in contradiction with the text [12].

Bone

Bone fragility manifests as fractures with minimal trauma and low mineral density. One of the Tunisian sisters had 23 fractures with normal PTH and vitamin D; her sister had multiple fractures and osteonecrosis of the femoral head at age 14 years, associated with hip dysplasia; the Turkish girl had demineralisation at 6 months and spontaneous fractures of the tibia and femur at 2 years [1, 2]. Three of the six Duclaux-Loras patients had fractures [2]. A North American patient had three fractures in childhood, with no information on the mechanism [15], and a Dutch patient had osteoporosis on dual-energy X-ray absorptiometry (DXA) at ages 14 and 25 years [18]. In patients with cholestasis and prolonged parenteral nutrition, metabolic bone disease of parenteral nutrition and vitamin D malabsorption are additional factors [11, 35].

Neurodevelopment, growth and other organs

Developmental delay and intellectual disability are mild in most and may be secondary to the deafness [1]. A French patient had severe intellectual disability and behavioural disorder, with visual loss due to unilateral anophthalmia, Peters anomaly and cataract, and a Palestinian boy also had Alazami syndrome [2, 16]. In a Chinese newborn girl, cranial ultrasound on day 18 showed hyperechogenicity of the basal ganglia and centrum semiovale, and neonatal brain injury was described in another child [17]. Growth retardation is frequent: the Tunisian sisters were 38.5 kg and 147.5 cm as adults (−3 and −2.5 standard deviations in the younger one) [1]. Isolated manifestations of uncertain relationship to the gene have been described: tubulopathy and poor glycaemic regulation in the Turkish girl; hydrocephalus due to aqueductal stenosis and vesicoureteric reflux in one of the Tunisian sisters [1]. There is no myopathy [1].

Published cases

PN: parenteral nutrition; F: female; M: male; IUGR: intrauterine growth restriction. The ear and bone data for the Duclaux-Loras patients follow the OMIM summary and the table of Wang and colleagues, because the supplementary material was not consulted [2, 12].

Natural history and treated disease

The published series describe treated patients, and there are no untreated natural history data. Intestinal severity depends on access to prolonged parenteral nutrition, enterectomy and intestinal transplantation, and the only recorded death occurred at 3 months from multiorgan failure [3]. The observed hepatic prognosis ranges from resolution in the first year to chronic or recurrent cholestasis treated with biliary diversion, with no published liver transplantation in patients with O2HE [1, 12, 15, 18]. In the allelic disorder Aagenaes syndrome, the natural history is documented in a Norwegian cohort spanning more than 50 years, with early death from haemorrhage before vitamin K prophylaxis and a current prognosis in which more than half of patients can expect a normal life expectancy [4, 36].

Aagenaes syndrome: picture of the allelic disorder

In the cohort of Almaas and colleagues (26 patients from 24 families, median age 19 years), all had cholestasis in childhood, ranging from a few self-limiting episodes to persistent cholestasis with disabling pruritus; 7 underwent liver transplantation (median at 7 months), 2 nasobiliary drainage and 2 partial external biliary diversion; of the 19 not transplanted, 15 had intermittent cholestasis [8]. Lower-limb lymphoedema appeared in all except two infants, with a median onset at 2.5 years, and upper-limb lymphoedema in 19; one patient had osteoporosis with fractures, two had periods of loose stools, cognition was normal in all and none had hearing loss [8]. Transplantation was more frequent in compound heterozygotes for the 5'UTR variant and an exonic allele (4 of 7) than in homozygotes (3 of 19) [8].

4. Clinical Recognition and Red Flags

When to suspect

In the prenatal period, the combination of polyhydramnios, diffuse intestinal dilatation and fetal growth restriction first suggests congenital chloride diarrhoea, but UNC45A deficiency should be included in the differential diagnosis; in a newborn girl with this picture, the absence of hypochloraemia and metabolic alkalosis after birth ruled out chloride diarrhoea and led to genetic testing [17]. In classic microvillus inclusion disease, polyhydramnios is rare, unlike congenital chloride diarrhoea and congenital sodium diarrhoea, and this contrast cannot be applied without reservation to UNC45A deficiency, in which it has already been described [17, 32].

In the newborn and young infant, suspicion arises in the presence of profuse watery diarrhoea from the first days that does not stop with fasting and requires parenteral nutrition, especially if cholestasis coexists [3, 13]. Jaundice persisting beyond 2 to 4 weeks requires measurement of conjugated bilirubin, and conjugated hyperbilirubinaemia is always pathological [37, 38]. In infant cholestasis, normal or low GGT with raised bile acids points to the progressive familial intrahepatic cholestases (PFIC), bile acid synthesis defects, arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome and the disorders of the myosin VB axis, among them UNC45A deficiency [11, 20, 37]. The combination of cholestasis with congenital diarrhoea, sensorineural hearing loss or recurrent fractures is the most specific sign [2].

In the older child and the adult, suspicion arises in the presence of recurrent episodes of jaundice, intense pruritus and weight loss with normal biochemistry between episodes, especially when testing of the classic genes of benign recurrent intrahepatic cholestasis and PFIC is negative, and when there are chronic loose stools with villous atrophy, hearing loss or osteoporosis [15, 18]. The two adults described had previous clinical diagnoses of benign recurrent intrahepatic cholestasis and PFIC type 1 and received the genetic diagnosis only at ages 20 and 30 years [15, 18]. In one woman, the episodes returned with combined oral contraceptives [15].

Universal newborn hearing screening, the investigation of fractures and the deafness clinic are other entry points. Severe or profound deafness affects about 1 in 1000 infants and is hereditary in at least 60% of cases in developed countries; about 35% of genetic causes are syndromic [39]. In the presence of recurrent fractures, assessment includes the age and mechanism of each fracture, exclusion of maltreatment, audiometry and bone biochemistry [40]. In a patient with deafness or fractures, a history of neonatal cholestasis or intractable diarrhoea in early childhood should raise the possibility of UNC45A deficiency [1].

Red flags and emergencies

High-volume diarrhoea causes dehydration, metabolic acidosis, hyponatraemia and renal impairment within a few hours, and one infant went into hypovolaemic shock at 3 weeks [3, 35]. Metabolic acidosis with lethargy and jaundice in a small-for-gestational-age newborn was treated as sepsis in a patient who died at 3 months [3]. Cholestasis with vitamin K malabsorption can cause haemorrhage, a cause of early death in the allelic disorder Aagenaes syndrome before systematic prophylaxis [4, 11]. Neonatal liver failure has been described and resolved at 4 months [1]. Fractures with minimal trauma, deterioration of hearing and language delay require targeted assessment [1].

Newborn screening

There is no newborn screening for UNC45A deficiency. Measurement of bile acids in newborn screening dried blood spots, in a liquid chromatography–mass spectrometry assay, showed raised bile acids in children with Alagille syndrome, Aagenaes syndrome and alpha-1 antitrypsin deficiency, with different profiles between diseases; the method has not been tested in O2HE [41]. Newborn hearing screening can detect congenital hearing loss, but some patients have late-detected hearing loss [1, 39].

5. Diagnosis: Criteria, Tests and Algorithms

Criteria

There are no formal diagnostic criteria. The diagnosis is molecular: two pathogenic or likely pathogenic variants in UNC45A, in trans, in a patient with at least one of the intestinal, hepatic, auditory or bone components [1, 2]. The presence of a 5'UTR allele points to Aagenaes syndrome [8].

Initial assessment of cholestasis

The joint guideline of the North American and European societies for paediatric gastroenterology, hepatology and nutrition recommends measuring total and conjugated bilirubin in any formula-fed infant with jaundice after 2 weeks (strong, high-quality evidence), allowing a wait until 3 weeks in a breastfed infant who looks well; a conjugated bilirubin above 1.0 mg/dL (17 µmol/L) is pathological and requires assessment (strong, high-quality evidence) [38]. Other authors propose investigating from 0.3 mg/dL (5 µmol/L) [11]. Direct observation of stool colour, abdominal ultrasound and liver biopsy interpreted by an experienced paediatric pathologist are part of the assessment, and biliary atresia must be excluded promptly [38]. In all patients with O2HE in whom the question arose, biliary atresia was excluded by surgical or laparoscopic exploration of the biliary tree [12, 18]. GGT distinguishes low- or normal-GGT cholestases from those with raised GGT; alkaline phosphatase is of little use, because it reflects growth and bone [11]. Cholesterol, alpha-1 antitrypsin, urinary and serum bile acids, very-long-chain fatty acids and spinal and chest radiographs and echocardiography (for Alagille syndrome) are part of the investigation of treatable and syndromic causes [37].

Assessment of congenital diarrhoea

Serum and faecal electrolytes, blood gases and urinary sodium and chloride point to diarrhoeas due to defective electrolyte transport: in congenital chloride diarrhoea there is hypochloraemia, hypokalaemia and metabolic alkalosis, and in MVID there is metabolic acidosis, hyponatraemia, low urinary sodium and hyperaldosteronism [17, 35]. Persistence of diarrhoea during bowel rest, prenatal expression, neonatal onset and extradigestive manifestations are the clinical elements that guide the diagnosis of congenital enteropathies, before histology [42]. Duodenal biopsy with PAS staining and immunohistochemistry for CD10, completed by transmission electron microscopy, shows microvillus inclusions, short and disorganised microvilli and subapical accumulation of vesicles; in classic MVID, accumulation of "secretory granules" is the first change and the inclusions appear in more mature cells [3, 32]. Rectal biopsy has been proposed as a simple method for early diagnosis of MVID [32]. Villous atrophy may be mild, as in one patient in the original series, and a minimally altered biopsy does not exclude the disease [2].

Auditory and bone assessment

All patients should have audiological assessment with brainstem auditory evoked potentials in infants and audiometry in children, because hearing loss may be congenital or detected late [1, 16]. Bone assessment includes calcium, phosphate, alkaline phosphatase, PTH and 25-hydroxyvitamin D, radiographs in the presence of fractures and DXA [18, 40]. In the original series, calcium-phosphate metabolism and vitamin D were normal in patients with fractures [1].

Genetic tests

The genetic approach may be a multigene cholestasis or congenital diarrhoea panel, or the exome or genome [11]. Inclusion of UNC45A in panels is not universal: the French paediatric cholestasis panel used in 602 patients includes the gene (NM_018671) and gave a definite diagnosis in 28.1%, but a North American patient had a negative commercial cholestasis panel and was diagnosed only by exome, and a Dutch patient had negative ABCB11 and ATP8B1 testing at age 20 years and was diagnosed only at 30 years by analysis of 116 cholestasis genes in the exome [15, 18, 21]. With a negative panel and clinical suspicion, the exome or genome is the next step [11]. When Aagenaes syndrome is suspected, the test must cover the 5'UTR region, which exome capture may not include; the founder variant was identified by genome sequencing and confirmed by Sanger [8].

Limitations of the tests

Exome sequencing does not reliably detect variants in untranslated and deep intronic regions, larger deletions and duplications or structural rearrangements, and a negative result does not exclude the diagnosis when the clinical picture is suggestive [8, 11]. Large 15q26 CNVs that include the gene are recorded in ClinVar with other phenotypes and are not a described mechanism of O2HE [9]. The proportion of variants detectable by a method is not the clinical sensitivity of the test for the disease, which is unknown given its rarity.

Interpretation and report

The report should state the gene, the transcript with version (NM_018671.5), the Human Genome Variation Society (HGVS) nomenclature at DNA and protein level, zygosity, phase confirmed by parental testing and the class according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [7, 11]. Because the older literature uses isoform 2 numbering (NM_001039675), comparison with published variants requires conversion through the genomic coordinates, and the same variant may appear under two names [12, 29]. Several published causal variants retain a VUS classification in ClinVar, so local classification should integrate the published functional data, segregation and phenotype [3, 9, 20]. Two VUS, or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis; in these cases, duodenal biopsy with electron microscopy and immunofluorescence for UNC45A and BSEP on liver biopsy provide functional support [3, 18]. The finding of other relevant variants on the exome should not close the investigation: a boy with O2HE also had Alazami syndrome, and in one patient in the original series the MYO15A variant was considered of uncertain significance for the deafness [1, 16].

Diagnostic algorithm

Prenatal and preimplantation diagnosis

Once the family's two variants are known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis are possible [11]. The ultrasound signs of intestinal dilatation and polyhydramnios are not specific, and in a pregnancy without a prior diagnosis refusal of amniocentesis delayed the diagnosis until the neonatal period [17].

6. Differential Diagnosis

Comparative table

Main differentials

The closest differential is MYO5B disease, which shares the mechanism: myosin VB is the client of the co-chaperone UNC45A, and both diseases cause MVID and low-GGT cholestasis [3, 20]. In the review by Aldrian and colleagues of 114 patients, MYO5B variants with no protein or early truncation gave predominant intestinal disease, those producing protein without residual function gave intestinal and hepatic disease, and those retaining residual function gave predominant cholestasis, classified as PFIC type 10 in OMIM [32]. O2HE is distinguished by hearing loss and bone fragility, although these may be absent or appear late, and only genetics separates the two diseases reliably [1, 19]. STX3-related MVID is associated with retinal dystrophy and STXBP2-related MVID with immunodeficiency, and these extraintestinal features help to guide testing [29].

Among the low-GGT cholestases, PFIC1 is the most difficult clinical differential, because it also combines cholestasis, diarrhoea and deafness; a patient with O2HE was clinically diagnosed with PFIC1 at age 4 years and received a molecular diagnosis only at 20 [11, 15]. Benign recurrent intrahepatic cholestasis, with episodes and normal intervals, was the initial diagnosis in another patient [18]. The facies of some patients resembles that of Alagille syndrome, which is distinguished by raised GGT and cholesterol, heart disease and butterfly vertebrae [14, 37].

Aagenaes syndrome is distinguished by lymphoedema, which may appear only after the first years, by the absence of diarrhoea, hearing loss and bone fragility, and by marked neonatal giant cell hepatitis [8]. In neonatal cholestasis in a family of Scandinavian origin, testing targeted at the 5'UTR is useful before the lymphoedema appears [8].

In neonatal diarrhoea with polyhydramnios, congenital chloride diarrhoea is the most likely diagnosis, but the absence of the typical electrolyte changes after birth requires broadening the investigation [17]. Trichohepatoenteric syndrome, also with intractable diarrhoea and liver disease, was one of the models of clinical variability invoked by the authors of the original description, and is distinguished by genetics [1]. In a patient with recurrent fractures and deafness, osteogenesis imperfecta is the first hypothesis; a history of cholestasis or neonatal diarrhoea and congenital or childhood sensorineural deafness point to UNC45A deficiency, and the bone fragility panel should be complemented by the exome when there is hepatic or intestinal involvement [1, 40].

Hearing loss in patients with neonatal cholestasis should not be attributed to hyperbilirubinaemia without investigation: unconjugated bilirubin above 250 µmol/L for a prolonged period is a known cause of deafness, but the hyperbilirubinaemia of O2HE is conjugated, and the deafness arose in patients without severe jaundice [1, 39].

7. Treatments and Risk Management Strategies

Principles and quality of evidence

There is no disease-modifying treatment or specific guideline for UNC45A deficiency, and no clinical trial has included patients with this disease [6, 43]. The evidence amounts to about 18 reports and small series, and the recommendations that follow extrapolate from the guidelines and labels of diseases with the same mechanism or the same manifestations: microvillus inclusion disease for the intestine, low-GGT intrahepatic cholestases (PFIC) for the liver and paediatric secondary osteoporosis for bone [35, 44–46]. The extrapolation is explicit for each drug. Treatment is organised by organ, in a centre with paediatric hepatology and gastroenterology, intestinal rehabilitation, transplantation, otorhinolaryngology and genetics, preferably linked to the European networks ERN RARE-LIVER, ERNICA and ERN TransplantChild [22–24, 37].

Intestine: acute phase

Neonatal diarrhoea with high-volume losses is a fluid and electrolyte emergency: intravenous replacement must compensate for losses that in MVID reach 150 to 400 mL/kg/day, with correction of metabolic acidosis, hyponatraemia and dehydration and monitoring of renal function [35]. Suspected sepsis is frequent at presentation and was the initial diagnosis in a patient who died at 3 months [3]. In the Chinese child with initial suspicion of chloride diarrhoea, empirical sodium chloride and potassium supplementation led to hyperkalaemia on day 12, a reminder that replacement should follow the electrolyte measurements and not the presumptive diagnosis [17].

Intestine: parenteral nutrition and diet

In MVID, parenteral nutrition (PN) and intravenous fluids are, in most patients, the only way to maintain growth, and fluid requirements often exceed twice maintenance [35]. Avitzur and colleagues, in a review by authors from the North American and European societies for paediatric gastroenterology, hepatology and nutrition, report from their experience that sodium in PN ranges from 9 to 17 mEq/kg/day and acetate from 6 to 16 mEq/kg/day, with enteral sodium bicarbonate to prevent acidosis; cycling of PN depends on clinical and laboratory signs of hydration [35]. Faecal losses cause copper and zinc deficiencies, and iron-deficiency anaemia often requires intravenous iron; iodine-free PN leads to iodine deficiency, and metabolic bone disease of PN requires additional enteral vitamin D, vitamin K and calcium [35]. A balanced lipid emulsion and cycling are recommended to reduce intestinal failure-associated liver disease, and aluminium in PN should be monitored [35]. Oral aversion appears early in these children [35].

Enteral tolerance varies more in UNC45A deficiency than in classic MVID. In one patient, the diarrhoea was controlled with exclusive enteral nutrition and ceased at age 10 years; in another, mild diarrhoea resolved at 6 months without prolonged PN; in a newborn girl, the combination of parenteral and enteral nutrition, montmorillonite, probiotics and a low-osmolality hydrolysed formula allowed weight gain from 3 weeks and transition to oral formula [3, 12, 17]. These symptomatic treatments have not been evaluated in a controlled manner. In patients with cholestasis, dietary fat should include medium-chain triglycerides (MCT), absorbed without bile acids, in formula or as oil [11]. The 2025 international biliary atresia guideline, applied by analogy to infant cholestasis, recommends energy of 130% to 150% of requirements, lipids with at least 30% MCT and at least 20% of energy as long-chain triglycerides, to avoid essential fatty acid deficiency, and protein of 2 to 5 g/kg/day [47].

Intestine: surgery and transplantation

When fluid and electrolyte balance cannot be maintained with PN, the options described are total enterectomy, performed in one patient at 20 months, and small bowel transplantation, performed in another patient [3]. In MVID of any cause, the proportion of patients with intestinal transplantation fell from 33.3% (23/69) between 1996 and 2010 to 12.9% (16/124) between 2011 and 2026, reflecting improvements in home PN and intestinal rehabilitation; comparisons between eras should be interpreted in that context [30]. In MYO5B disease, liver disease may be transient, progressive or recurrent, and should be reassessed before any transplantation decision; liver transplantation does not correct the extrahepatic manifestations [11].

Liver: general measures and fat-soluble vitamins

Cholestasis causes malabsorption of vitamins A, D, E and K, with a risk of haemorrhage from coagulopathy, poor weight gain, rickets and neuropathy, and supplementation and regular measurement are mandatory [10, 11]. Because there are no published doses for O2HE, those of the biliary atresia guideline are used, a paediatric cholestasis treated with the same supplements: vitamin A 5000 IU/day up to 10 kg and 10,000 IU/day above 10 kg, with retinol and retinol-binding protein every 3 to 6 months; vitamin D3 2000 to 5000 IU/day, considering a 25-hydroxyvitamin D below 75 nmol/L (30 ng/mL) as insufficiency and below 50 nmol/L (20 ng/mL) as deficiency, with PTH, calcium and phosphorus; vitamin E in the water-soluble form tocopherol polyethylene glycol succinate (TPGS) 15 to 25 IU/kg/day; vitamin K 2 to 5 mg/day orally, or 1 to 10 mg intravenously or intramuscularly if protein induced by vitamin K absence (PIVKA-II) exceeds 3 ng/mL, adjusting according to the international normalised ratio (INR) [47]. In an infant with O2HE, the authors used vitamin A and D 1800 IU/day and vitamin E 25 mg/day during and after admission [12]. Colestyramine and IBAT inhibitors worsen vitamin malabsorption, and the odevixibat label requires measurement of vitamins A, D and E and INR at baseline and during treatment [48, 49].

Liver: treatment of pruritus

Cholestatic pruritus is the symptom that most disrupts the lives of patients with O2HE and the most constant in the cases reviewed [18]. Treatment follows that of low-GGT intrahepatic cholestases, in steps: skin care, ursodeoxycholic acid, rifampicin and bile acid sequestrant resins, antihistamines, sertraline, naltrexone or naloxone, and IBAT inhibitors, with surgical biliary diversion and liver transplantation for refractory cases [11, 44, 45]. The European expert opinion on PFIC proposes starting with odevixibat 40 µg/kg/day for 12 weeks, increasing to 120 µg/kg/day if the response is insufficient, and moving to sequential trials of ursodeoxycholic acid, rifampicin, sertraline, ondansetron, colestyramine, phenobarbital, naltrexone and antihistamines if there is no improvement, quantifying pruritus with a validated instrument before starting [45]. The European Association for the Study of the Liver (EASL) guideline recommends considering IBAT inhibition to reduce pruritus before transplantation in patients with BSEP deficiency and missense variants (level of evidence 2, strong recommendation) [44].

The specific experience with UNC45A deficiency favours odevixibat. In a 31-year-old man with recurrent episodes of cholestasis since birth, despite colestyramine, simvastatin and rifampicin, odevixibat 38.5 µg/kg/day, started after an episode, eliminated the episodes of pruritus and weight loss for 2.5 years, with a transient rise in aminotransferases [18]. In a 20-year-old woman with an adult relapse refractory to colestyramine, colestipol, rifampicin, ursodeoxycholic acid and phenobarbital, odevixibat normalised bilirubin, aminotransferases and bile acids (which exceeded 1350 µmol/L) and ended the pruritus for about 1.5 years, without changing the diarrhoea or malabsorption [15]. In five children with MYO5B-related PFIC refractory to rifampicin and ursodeoxycholic acid, doses of 37.2 to 120 µg/kg/day lowered bile acids to less than 10 µmol/L and bilirubin to less than 15 µmol/L within 6 months, with maintenance for 22 to 39 months in four, and one relapse without response to reintroduction after infectious gastroenteritis [50]. IBAT inhibitors presuppose a preserved enterohepatic circulation and some preserved canalicular transport; the mechanism of UNC45A deficiency, in which BSEP exists but does not reach the membrane, is compatible with a response [20, 51]. Diarrhoea is the most frequent adverse effect of these drugs (39% with odevixibat 40 µg/kg versus 10% with placebo in the PEDFIC1 trial; 57.4% with maralixibat versus 19.6% in the MARCH-PFIC trial), and maralixibat has not been studied in patients with chronic diarrhoea requiring intravenous fluids, a frequent situation in O2HE [49, 52]. In the two adults with O2HE treated, no worsening of diarrhoea was reported [15, 18].

The patients of Imhann and colleagues did not receive ursodeoxycholic acid, because of the concomitant diarrhoea and the limited effect described in low-GGT cholestasis, or bezafibrate [18]. In an infant with raised-GGT cholestasis, ursodeoxycholic acid 50 mg/day, combined with vitamins, glycyrrhizin and ademetionine, accompanied biochemical normalisation, without the effect being attributable to it in a cholestasis that resolves spontaneously in other patients [12]. Partial internal biliary diversion improved the intractable pruritus of the two Tunisian sisters, and partial ileal diversion at age 4 years kept one patient free of pruritus for more than a decade [1, 15]. Partial external biliary diversion drains 30% to 50% of bile and has better results when bile acids normalise in the first year and when it is performed before cirrhosis; partial ileal exclusion may cause vitamin B12 malabsorption and diarrhoea, a relevant drawback in O2HE [11]. Liver transplantation is the option for refractory pruritus and end-stage liver disease, but does not correct the extrahepatic manifestations and has not been published in patients with O2HE [11].

Dosage of the drugs used

The doses of odevixibat, maralixibat, rifampicin, colestyramine, vitamins and zoledronic acid in children are extrapolations from analogous conditions and are outside the approved indications for O2HE. The reference dose is that of the cited guideline or expert opinion, and the label serves for comparison [45–47].

Regulatory status of IBAT inhibitors

The sources consulted do not include reimbursement or national authorisation data in Portugal (INFARMED) or Brazil (ANVISA) for these drugs.

Bone

Prevention of bone disease rests on correcting cholestasis, vitamin D and calcium malabsorption and the deficiencies of PN, with enteral supplementation of vitamin D, vitamin K and calcium when PN does not provide them in sufficient quantity [35, 47]. The bone fragility of O2HE occurred with normal calcium, phosphate, PTH and vitamin D, so supplementation is not enough [1]. Bisphosphonates are the pharmacological treatment of fragility fractures in children, as part of a multidisciplinary approach with physiotherapy, occupational therapy and orthopaedics [40, 46]. In an adult with O2HE and osteoporosis since age 14 years, zoledronic acid with calcium and vitamin D improved lumbar spine mineral density and, to a lesser extent, that of the proximal femur [18]. IBAT inhibitors have been associated with fractures in open-label studies, and starting them in a patient with bone fragility requires prior optimisation of vitamin D [49, 52].

Hearing, language and development

Sensorineural hearing loss is treated with hearing aids or cochlear implants, according to severity: an adult with moderate hearing loss received a hearing aid, one patient had cochlear implants in childhood, and severe or profound deafness leads many children to cochlear implantation [15, 18, 39]. Because language delay may be secondary to deafness, early auditory rehabilitation and speech and language therapy are part of the treatment of developmental delay [1]. Neurodevelopmental assessment and educational support are tailored to each patient, given that intellectual disability ranges from absent to severe [2, 15].

Investigational treatment and gene therapies

There is no gene therapy, oligonucleotide therapy or UNC45A-targeted drug in clinical study, and a ClinicalTrials.gov search in November 2026 found no study involving the gene or the syndrome [43]; the absence of registrations does not show that there is no unpublished preclinical work. The only proposed therapeutic target comes from cellular studies: in HepG2 hepatocytes with the p.(Arg98Trp) variant, increasing HSPA1A by heat shock, by the compound TRC051384 or by paracetamol restored the positioning of MYO5B+/RAB11A+ endosomes and the canalicular localisation of BSEP, but not in a form of UNC45A lacking the TPR domain [20]. The authors themselves stress that the paracetamol concentration used (5 mM, about 756 µg/mL) far exceeds the therapeutic plasma concentration (10 to 20 µg/mL) and the toxic concentration (more than 150 µg/mL), that HepG2 cells do not reproduce the hepatic response to paracetamol and that hepatic induction of HSPA1A by drugs reflects injury; they propose instead direct delivery of HSPA1A to hepatocytes of the mid-zone of the acinus [20]. This is a preclinical result, specific to one variant, with no clinical application. In MVID in general, a phase 2/3 trial of the antisecretory agent crofelemer as an oral powder (NCT06721871; 1, 3 and 10 mg/kg per dose three times a day, in crossover with placebo) enrolled six children with genetic or histological MVID and PN covering at least half of fluid requirements, with no results published to date and completion expected in December 2026; it is not known whether it included patients with UNC45A deficiency [43].

Table of relevant trials by analogy

None of these trials included patients with confirmed O2HE, and the IBAT inhibitor trials excluded, in the case of odevixibat, forms of BSEP deficiency without functional protein [49]. The results cannot be transposed quantitatively to O2HE, nor compared with each other, because the pruritus instruments, populations and durations differ. The experience in O2HE amounts to two adults with a clinical response, with no published failures, which may reflect publication bias [15, 18].

Developments in the last 12 months

Drugs and situations to avoid

Oestrogens triggered an adult relapse of cholestasis with bile acids above 1350 µmol/L in a patient with O2HE, and discontinuation of contraceptives was recommended [15]; in the allelic disorder Aagenaes syndrome, pregnancy, hormonal contraceptives and the menstrual cycle are triggers of pruritus [8]. The choice of contraceptive method should take this risk into account, and any start of oestrogen-containing hormonal contraception justifies biochemical monitoring. Paracetamol should not be used with therapeutic intent to correct the BSEP defect, because the in vitro effect required toxic concentrations [20]. Rifampicin and IBAT inhibitors require hepatic monitoring [11, 49]. Empirical electrolyte supplementation without electrolyte measurements can cause hyperkalaemia [17].

Pregnancy, lactation, perioperative care and transition

There are no reports of pregnancy in women with O2HE in the sources consulted. Pregnancy is a trigger of cholestatic pruritus in Aagenaes syndrome, and by analogy should be monitored with bile acids and liver tests [8]. Odevixibat is not recommended during pregnancy according to the European label, which requires effective contraception in women of childbearing potential, and it caused cardiovascular malformations in rabbits; maralixibat has minimal absorption, but the European label prefers to avoid it in pregnancy [49, 51, 53]. In the perioperative period, coagulation should be corrected before any procedure — the biliary atresia guideline recommends vitamin K 0.2 to 0.3 mg/kg intravenously 1 to 2 hours before surgery (strong recommendation, very low-quality evidence) — and fluid balance must take faecal losses into account [35, 47]. Transition to adult medicine should maintain hepatic, bone and auditory monitoring: one patient moved to adult hepatology at age 18 years with episodes 2 to 3 times a year, and another had a relapse in adulthood after more than a decade without symptoms [15, 18].

Guideline recommendations and divergences

No guideline mentions UNC45A deficiency. The NASPGHAN/ESPGHAN guideline on infant cholestasis guides the initial investigation and the exclusion of biliary atresia [38]. The 2024 EASL guideline and the European expert opinion on PFIC guide the treatment of pruritus, with divergences that matter here: the expert opinion places odevixibat as first line, whereas the GeneReviews overview and earlier practice start with ursodeoxycholic acid, rifampicin and resins [11, 44, 45]. The labels diverge between jurisdictions: the FDA contraindicates IBAT inhibitors in hepatic decompensation, the EU only in hypersensitivity; the FDA approves odevixibat from 3 months and the EU from 6 months in PFIC; and the EU does not expect patients without functional BSEP to respond [49, 51]. For O2HE, the choice between odevixibat and the classic treatments should weigh the underlying diarrhoea, which ursodeoxycholic acid and IBAT inhibitors can worsen, against the positive experience in two adults [15, 18].

8. Reproductive Options and Family Counselling

Recurrence risk

UNC45A deficiency is autosomal recessive. When both parents are carriers, each child has, at each conception, a 25% probability of being affected, 50% of being an asymptomatic carrier and 25% of inheriting neither variant [11]. Carriers are healthy, even with a 45% to 52% reduction of the protein in blood cells [1, 27]. In populations with consanguinity, the probability of both parents carrying the same variant increases: four of 17 patients reviewed had consanguineous parents, and three Turkish patients from two consanguineous families were homozygous for the same p.(Leu237Pro) [3, 19]. The offspring of a patient with O2HE are obligate heterozygotes; the risk of an affected child exists only if the partner is also a carrier, and in that case it is 50% [11]. The parents' siblings have a 50% probability of being carriers [11].

Confirmation of phase and particular situations

Parental testing is needed to confirm that the two variants are in trans and to calculate the risk accurately [11]. If only one parent is a carrier, with paternity and maternity confirmed, the possibilities are a de novo variant in the patient, germline mosaicism in a parent or uniparental isodisomy [11]. In O2HE, the origin of one of the variants in the first family described remained ambiguous (de novo in the text, maternal in the figure of the paper), and in a Tunisian family two substitutions were on the same paternal allele, a case in which phase must be demonstrated before counting them as two alleles [5]. In the family with Aagenaes syndrome and possible mother-to-daughter transmission, OMIM accepts a heterozygous parent with a carrier partner as an explanation [4].

Carrier testing and founder alleles

Carrier testing in relatives requires prior identification of the family's variants [11]. The c.-98G>T variant of Aagenaes syndrome has an allele frequency of 0.0011 to 0.002 in Scandinavian databases, 50 to 100 times the global frequency, and a partner of a carrier of Scandinavian origin may benefit from targeted testing for this variant [8]. In O2HE no founder variant has been demonstrated, but p.(Leu237Pro) recurred in Turkish and Chinese families and p.(Arg98Trp) in Turkish, Chinese and Dutch patients [19, 20].

Prenatal and preimplantation diagnosis

Once the two variants are known, prenatal diagnosis and preimplantation genetic diagnosis are possible, and the appropriate time to discuss these options is before pregnancy [11]. Prenatal ultrasound may show polyhydramnios, intestinal dilatation and growth restriction, but these signs are neither specific nor constant [3, 17]. Views on prenatal diagnosis vary between professionals and families, and the decision is personal [11].

Counselling of minors and young adults

Counselling on risks and reproductive options should be offered to young adults who are affected, carriers or at risk of being carriers [11]. Determining carrier status in a healthy minor sibling does not change their clinical monitoring, and can be deferred until the age at which they can decide for themselves. Diagnostic testing of symptomatic siblings or of newborns of at-risk couples is different and is justified by the possibility of early nutritional and vitamin treatment and of auditory and bone monitoring [1, 11]. Affected women should be informed of the role of oestrogens and pregnancy as triggers of cholestasis [8, 15].

9. Special Considerations: Population Diversity and Epidemiology

Prevalence and what each study measures

There is no estimate of the prevalence or incidence of O2HE. The available figures are counts of published cases: 14 patients up to 2025 according to Imhann and colleagues, 17 patients from 15 families according to Wang and colleagues in 2026, and about 18 in the sources consulted for this article, counting the cases described subsequently [18, 19]. These counts measure publication, not frequency. The presence of pathogenic UNC45A variants in population databases and the late diagnosis of two adults suggest underdiagnosis [15, 18]. The French paediatric cholestasis panel applied to 602 patients includes the gene, and the study reports no patients with UNC45A variants among the 169 definite diagnoses, which is compatible with a very low frequency among genetic cholestases [21]. In MVID of any cause, UNC45A ranks fourth in frequency, after MYO5B, STXBP2 and STX3 [30]. In the allelic disorder Aagenaes syndrome, the incidence in Norway was 1 in 80,980 live births between 1996 and 2022, with 19 patients in 1,538,627 births, and about 100 cases have been described worldwide [8].

Geographical distribution and populations

The patients with O2HE described come from France, the United Kingdom, the French Antilles, Turkey (four families), Tunisia, China (five patients), Russia, the United States, Palestine and the Netherlands [1, 3, 12–19]. The concentration of homozygous patients in consanguineous Turkish families reflects consanguinity and not a demonstrated founder variant [3, 19]. Aagenaes syndrome is concentrated in south-western Norway, with many patients descended from a common ancestor, and is very rare outside Scandinavia [8, 58]. The sources consulted include no patients from Portugal or Brazil, which does not show that none exist.

Special populations

Preterm infants and newborns with growth restriction make up a relevant part of the patients described [3, 16, 17]. Children on prolonged PN are exposed to the complications of intestinal failure and PN, including intestinal failure-associated liver disease, metabolic bone disease, micronutrient deficiencies and aluminium toxicity [35]. Patients with deafness need adapted communication in consultations and in consent. Women of childbearing age need counselling on contraception and pregnancy [15, 51].

European networks and patient organisations

The European Reference Network for rare liver diseases (ERN RARE-LIVER) includes the paediatric cholestasis centres, among them the Bicêtre reference centre, which developed the cholestasis panel including UNC45A [21, 22]. The ERNICA network covers rare inherited and congenital digestive diseases, including congenital enteropathies and intestinal failure, and ERN TransplantChild covers paediatric intestinal and liver transplantation [23, 24]. The Children's Liver Disease Foundation, in the United Kingdom, supports families of children with chronic liver disease [37], and the French patient association Association Romy – La vie par un fil funded part of the founding work [1].

10. Illustrative Clinical Case

Imhann, Zhou, Malcolm and colleagues, from the University Medical Center Groningen, described in 2025 a 33-year-old man with episodes of severe pruritus, diarrhoea and weight loss since birth [18]. In the first 10 days of life he developed jaundice and completely white diarrhoea. On day 28, aspartate aminotransferase was 35 U/L, alanine aminotransferase 30 U/L, alkaline phosphatase 902 U/L, GGT 27 U/L (reference 0–40), total bilirubin 175 µmol/L and direct bilirubin 137 µmol/L, a picture of low-GGT cholestasis. Liver biopsy on day 32 showed severe histological cholestasis with enlarged portal tracts and ductular proliferation, and surgical exploration of the biliary tree excluded biliary atresia [18].

At age 2 years, recurrent episodes of jaundice, raised bile acids and pruritus led to a diagnosis of benign recurrent intrahepatic cholestasis. Colestyramine and simvastatin, and later rifampicin, gave partial relief of the pruritus without changing the frequency of the episodes, and between them biochemistry was normal. Loose stools up to six times a day persisted, with several admissions for dehydration and weight loss, and endoscopies showed villous atrophy with no identified cause. At age 10 years he had an exacerbation with bilirubin up to 270 µmol/L for 7 months, and a new biopsy showed parenchyma of normal architecture with canalicular cholestasis and bile pigment in hepatocytes [18]. At age 18 years he moved to adult gastroenterology and hepatology, with episodes of jaundice, pruritus, diarrhoea and weight loss on average 2 to 3 times a year, each lasting several weeks. At age 20 years, ABCB11 and ATP8B1 testing was negative. Dual-energy X-ray absorptiometry showed osteoporosis at ages 14 and 25 years, and zoledronic acid with calcium and vitamin D improved lumbar spine mineral density and, to a lesser extent, that of the proximal femur [18].

At age 30 years, analysis of 116 cholestasis and liver failure genes in the exome identified two variants in UNC45A: the maternal missense variant c.292C>T p.(Arg98Trp), already described in another patient with O2HE, and the paternal nonsense variant c.592C>T p.(Gln198Ter), which was novel; both were present in heterozygosity in population databases [18]. The two variants are described on the MANE transcript NM_018671.5 and correspond, in the GRCh38 reference genome, to NC_000015.10:g.90936326C>T and g.90940378C>T [7]. Targeted otorhinolaryngological assessment found moderate bilateral sensorineural hearing loss, treated with a hearing aid. Immunofluorescence of the liver biopsy stored since age 10 years showed reduced UNC45A expression and reduced expression and abnormal localisation of BSEP in hepatocytes (figure 1A, https://pmc.ncbi.nlm.nih.gov/articles/PMC13019544/figure/fig1/), and the diagnosis of O2HE was established [18]. The same tissue was later used to demonstrate the zonated BSEP defect in the mid-zone of the acinus [20].

Previous treatments for the pruritus had been insufficient. The team did not start ursodeoxycholic acid, because of the diarrhoea and the limited effect described in low-GGT cholestasis, or bezafibrate, as no effect on the diarrhoea was expected, and opted for the IBAT inhibitor odevixibat, obtained through compassionate use, at a dose of 38.5 µg/kg/day, started at age 31 years after bile acids and bilirubin had normalised following an episode [18]. Over 2.5 years of follow-up, there were no new episodes of pruritus or weight loss. Aminotransferases rose moderately and transiently, a known adverse effect of the drug, and bilirubin and total bile acids remained low; the ratio of cholic acid to chenodeoxycholic acid did not normalise (reference above 0.6) and the ratio of glycine- to taurine-conjugated bile acids fell transiently (figure 1C–F) [18, 49].

The case brings together the elements that delay diagnosis: low-GGT cholestasis interpreted for decades as benign recurrent intrahepatic cholestasis, an enteropathy attributed to idiopathic villous atrophy, osteoporosis treated without an underlying diagnosis and hearing loss sought only after the genetic result [18]. The use of odevixibat is off-label, in an adult, at a dose slightly below the starting dose in PFIC, and the response of a single patient does not define efficacy in O2HE; the applicable guideline and labels require frequent hepatic monitoring in the first months, which in this patient detected the transient rise in aminotransferases [45, 49]. The typical intestinal histology of another patient, with subapical accumulation of PAS and CD10 and, on electron microscopy, microvillus inclusions, basolateral microvilli and enlarged lysosomes, is illustrated in figure 2 of Duclaux-Loras and colleagues (https://pmc.ncbi.nlm.nih.gov/articles/PMC9106349/figure/F2/) [3].

11. Prognosis and Long-Term Follow-Up

Prognosis

Prognosis depends mainly on the severity of intestinal disease in the first year and on access to prolonged PN, intestinal rehabilitation and transplantation. Among about 18 patients described, one died at 3 months from multiorgan failure, one underwent total enterectomy at 20 months and remained on cyclic PN at 4 years, another underwent small bowel transplantation, and others became free of PN in childhood (with cessation of diarrhoea at 6 months in one patient and at 10 years in another) [3, 12]. There are adult patients aged 18, 20, 21, 23 and 33 years [1, 3, 15, 18]. The liver disease has had no published liver transplantation and has progressed to resolution, to chronic cholestasis with pruritus treated by biliary diversion or to recurrent episodes into adulthood; in one patient, pericellular and periductal fibrosis with Mallory-Denk bodies at age 18 years indicates that the disease can progress [1, 2]. Hearing loss may be detected only in adolescence or adulthood, and bone fragility may manifest from 6 months into adulthood [1, 18]. In Aagenaes syndrome, more than half of Norwegian patients can expect a normal life expectancy with nutritional and vitamin treatment, and remission of liver disease by 2 to 2.5 years is associated with a better prognosis [4, 36]. There are no survival or quality-of-life data for O2HE.

Surveillance table

There is no published surveillance protocol for O2HE. The table adapts the surveillance of paediatric genetic cholestases, MVID and paediatric secondary osteoporosis to the manifestations described, and the frequencies proposed by the European expert opinion on PFIC are acknowledged by the authors as arbitrary [45].

Transition and adult follow-up

Transition should maintain hepatic, bone and auditory monitoring, because cholestatic relapses and detection of deafness have occurred in adulthood, and because oestrogens and pregnancy are triggers [8, 15, 18]. Patients who have undergone biliary or ileal diversion need follow-up for vitamin B12 and fat-soluble vitamin malabsorption [11].

12. Summary and Final Considerations

UNC45A deficiency is an autosomal recessive disorder of epithelial apical trafficking, caused by loss of function of a co-chaperone that, together with the chaperones HSP90 and HSP70, keeps myosin VB and other myosins folded and functional. Two coding variants cause osteo-oto-hepato-enteric syndrome, with microvillus inclusion-type congenital diarrhoea, intrahepatic cholestasis usually with low GGT, sensorineural hearing loss and bone fragility, in variable combinations; an allele in the 5' untranslated region causes Aagenaes syndrome, with neonatal cholestasis and lymphoedema and without the intestinal, auditory and bone components. About 18 patients with O2HE have been described since 2018, with diarrhoea in 87.5% and cholestasis in 81.3% of the patients reviewed, and two adults were diagnosed only at ages 20 and 30 years.

The diagnosis is molecular and requires a panel that includes the gene, or the exome or genome; the older literature numbers the variants on an isoform 15 amino acids shorter, and the same recurrent variant appears as p.Arg83Trp and as p.(Arg98Trp). Several causal variants retain a classification of uncertain significance in ClinVar, and duodenal biopsy with electron microscopy and hepatic BSEP immunofluorescence provide functional support. Treatment is supportive and organised by organ: fluid and electrolyte replacement and PN, enterectomy or intestinal transplantation in severe forms, fat-soluble vitamins and MCT, stepwise treatment of pruritus with biliary diversion when needed, bisphosphonates and auditory rehabilitation. Ileal bile acid transporter inhibitors, used off-label, controlled pruritus and cholestatic episodes in two adults, at the cost of the hepatic monitoring required by the labels. The HSP70 target proposed for the p.(Arg98Trp) variant is preclinical. Surveillance should continue into adulthood, especially for hearing, bone and cholestatic relapses triggered by oestrogens.

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